bims-miptne 2024-07-21 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2024–07–21
six papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

L-carnitine co-administration prevents colistin-induced mitochondrial permeability transition and reduces the risk of acute kidney injury in mice.
Mitochondrial dysfunction and its association with age-related disorders.
Deciphering the mitochondria-inflammation axis: Insights and therapeutic strategies for heart failure.
Mitochondrial inhibitors: a new horizon in breast cancer therapy.
ATAD1 prevents clogging of TOM and damage caused by un-imported mitochondrial proteins.
Autophagy as a Therapeutic Target in Breast Tumors: The Cancer stem cell perspective.

Sci Rep. 2024 Jul 16. 14(1): 16444

L-carnitine co-administration prevents colistin-induced mitochondrial permeability transition and reduces the risk of acute kidney injury in mice.

Sophia L Samodelov, Zhibo Gai, Francesca De Luca, Klara Haldimann, Sven N Hobbie, Daniel Müller, Gerd A Kullak-Ublick, Michele Visentin.

  Colistin is a polymyxin antibiotic currently experiencing renewed clinical interest due to its efficacy in the treatment of multidrug resistant (MDR) bacterial infections. The frequent onset of acute dose-dependent kidney injury, with the potential of leading to long-term renal damage, has limited its use and hampered adequate dosing regimens, increasing the risk of suboptimal plasma concentrations during treatment. The mechanism of colistin-induced renal toxicity has been postulated to stem from mitochondrial damage, yet there is no direct evidence of colistin acting as a mitochondrial toxin. The aim of this study was to evaluate whether colistin can directly induce mitochondrial toxicity and, if so, uncover the underlying molecular mechanism. We found that colistin leads to a rapid permeability transition of mitochondria isolated from mouse kidney that was fully prevented by co-incubation of the mitochondria with desensitizers of the mitochondrial transition pore cyclosporin A or L-carnitine. The protective effect of L-carnitine was confirmed in experiments in primary cultured mouse tubular cells. Consistently, the relative risk of colistin-induced kidney damage, calculated based on histological analysis as well as by the early marker of tubular kidney injury, Kim-1, was halved under co-administration with L-carnitine in vivo. Notably, L-carnitine neither affected the pharmacokinetics of colistin nor its antimicrobial activity against relevant bacterial strains. In conclusion, colistin targets the mitochondria and induces permeability transition thereof. L-carnitine prevents colistin-induced permeability transition in vitro. Moreover, L-carnitine co-administration confers partial nephroprotection in mice treated with colistin, without interfering with its pharmacokinetics and antibacterial activity.

Keywords:  Colistin; Drug-induced kidney injury; Kim-1; L-carnitine; Mitochondria; Nephrotoxicity polymyxins; Proximal tubule

DOI:  https://doi.org/10.1038/s41598-024-67171-x
Front Physiol. 2024 ;15 1384966

Mitochondrial dysfunction and its association with age-related disorders.

Indumathi Somasundaram, Samatha M Jain, Marcel Blot-Chabaud, Surajit Pathak, Antara Banerjee, Sonali Rawat, Neeta Raj Sharma, Asim K Duttaroy.

  Aging is a complex process that features a functional decline in many organelles. Various factors influence the aging process, such as chromosomal abnormalities, epigenetic changes, telomere shortening, oxidative stress, and mitochondrial dysfunction. Mitochondrial dysfunction significantly impacts aging because mitochondria regulate cellular energy, oxidative balance, and calcium levels. Mitochondrial integrity is maintained by mitophagy, which helps maintain cellular homeostasis, prevents ROS production, and protects against mtDNA damage. However, increased calcium uptake and oxidative stress can disrupt mitochondrial membrane potential and permeability, leading to the apoptotic cascade. This disruption causes increased production of free radicals, leading to oxidative modification and accumulation of mitochondrial DNA mutations, which contribute to cellular dysfunction and aging. Mitochondrial dysfunction, resulting from structural and functional changes, is linked to age-related degenerative diseases. This review focuses on mitochondrial dysfunction, its implications in aging and age-related disorders, and potential anti-aging strategies through targeting mitochondrial dysfunction.

Keywords:  ROS production; chromosomal aberrations; mitochondrial DNA; mitochondrial dysfunction; mitophagy

DOI:  https://doi.org/10.3389/fphys.2024.1384966
Int Immunopharmacol. 2024 Jul 17. pii: S1567-5769(24)01218-9. [Epub ahead of print]139 112697

Deciphering the mitochondria-inflammation axis: Insights and therapeutic strategies for heart failure.

Baile Zuo, Xiu Fan, Dawei Xu, Liping Zhao, Bi Zhang, Xiaoyan Li.

  Heart failure (HF) is a clinical syndrome resulting from left ventricular systolic and diastolic dysfunction, leading to significant morbidity and mortality worldwide. Despite improvements in medical treatment, the prognosis of HF patients remains unsatisfactory, with high rehospitalization rates and substantial economic burdens. The heart, a high-energy-consuming organ, relies heavily on ATP production through oxidative phosphorylation in mitochondria. Mitochondrial dysfunction, characterized by impaired energy production, oxidative stress, and disrupted calcium homeostasis, plays a crucial role in HF pathogenesis. Additionally, inflammation contributes significantly to HF progression, with elevated levels of circulating inflammatory cytokines observed in patients. The interplay between mitochondrial dysfunction and inflammation involves shared risk factors, signaling pathways, and potential therapeutic targets. This review comprehensively explores the mechanisms linking mitochondrial dysfunction and inflammation in HF, including the roles of mitochondrial reactive oxygen species (ROS), calcium dysregulation, and mitochondrial DNA (mtDNA) release in triggering inflammatory responses. Understanding these complex interactions offers insights into novel therapeutic approaches for improving mitochondrial function and relieving oxidative stress and inflammation. Targeted interventions that address the mitochondria-inflammation axis hold promise for enhancing cardiac function and outcomes in HF patients.

Keywords:  Calcium; Heart failure (HF); Inflammation; Mitochondria; Reactive oxygen species (ROS)

DOI:  https://doi.org/10.1016/j.intimp.2024.112697
Front Pharmacol. 2024 ;15 1421905

Mitochondrial inhibitors: a new horizon in breast cancer therapy.

Yalan Yan, Sijie Li, Lanqian Su, Xinrui Tang, Xiaoyan Chen, Xiang Gu, Guanhu Yang, Hao Chi, Shangke Huang.

  Breast cancer, due to resistance to standard therapies such as endocrine therapy, anti-HER2 therapy and chemotherapy, continues to pose a major health challenge. A growing body of research emphasizes the heterogeneity and plasticity of metabolism in breast cancer. Because differences in subtypes exhibit a bias toward metabolic pathways, targeting mitochondrial inhibitors shows great potential as stand-alone or adjuvant cancer therapies. Multiple therapeutic candidates are currently in various stages of preclinical studies and clinical openings. However, specific inhibitors have been shown to face multiple challenges (e.g., single metabolic therapies, mitochondrial structure and enzymes, etc.), and combining with standard therapies or targeting multiple metabolic pathways may be necessary. In this paper, we review the critical role of mitochondrial metabolic functions, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid cycle, and fatty acid and amino acid metabolism, in metabolic reprogramming of breast cancer cells. In addition, we outline the impact of mitochondrial dysfunction on metabolic pathways in different subtypes of breast cancer and mitochondrial inhibitors targeting different metabolic pathways, aiming to provide additional ideas for the development of mitochondrial inhibitors and to improve the efficacy of existing therapies for breast cancer.

Keywords:  breast cancer; cancer subtype; metabolic reprogramming; mitochondrial inhibitors; tumor progression

DOI:  https://doi.org/10.3389/fphar.2024.1421905
Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00802-7. [Epub ahead of print]43(8): 114473

ATAD1 prevents clogging of TOM and damage caused by un-imported mitochondrial proteins.

John Kim, Madeleine Goldstein, Lauren Zecchel, Ryan Ghorayeb, Christopher A Maxwell, Hilla Weidberg.

  Mitochondria require the constant import of nuclear-encoded proteins for proper functioning. Impaired protein import not only depletes mitochondria of essential factors but also leads to toxic accumulation of un-imported proteins outside the organelle. Here, we investigate the consequences of impaired mitochondrial protein import in human cells. We demonstrate that un-imported proteins can clog the mitochondrial translocase of the outer membrane (TOM). ATAD1, a mitochondrial ATPase, removes clogged proteins from TOM to clear the entry gate into the mitochondria. ATAD1 interacts with both TOM and stalled proteins, and its knockout results in extensive accumulation of mitochondrial precursors as well as decreased protein import. Increased ATAD1 expression contributes to improved fitness of cells with inefficient mitochondrial protein import. Overall, we demonstrate the importance of the ATAD1 quality control pathway in surveilling protein import and its contribution to cellular health.

Keywords:  AAA ATPase; ATAD1; CP: Cell biology; CP: Metabolism; TOM clogging; mitochondrial protein import; mitochondrial stress; protein quality control; proteotoxicity

DOI:  https://doi.org/10.1016/j.celrep.2024.114473
Autophagy Rep. 2024 Dec 31. pii: 27694127.2024.2358648. [Epub ahead of print]3(1):

Autophagy as a Therapeutic Target in Breast Tumors: The Cancer stem cell perspective.

Sana Raza, Jawed Akhtar Siddiqui, Anubhav Srivastava, Naibedya Chattopadhyay, Rohit Anthony Sinha, Bandana Chakravarti.

  Breast cancer is a heterogeneous disease, with a subpopulation of tumor cells known as breast cancer stem cells (BCSCs) with self-renewal and differentiation abilities that play a critical role in tumor initiation, progression, and therapy resistance. The tumor microenvironment (TME) is a complex area where diverse cancer cells reside creating a highly interactive environment with secreted factors, and the extracellular matrix. Autophagy, a cellular self-digestion process, influences dynamic cellular processes in the tumor TME integrating diverse signals that regulate tumor development and heterogeneity. Autophagy acts as a double-edged sword in the breast TME, with both tumor-promoting and tumor-suppressing roles. Autophagy promotes breast tumorigenesis by regulating tumor cell survival, migration and invasion, metabolic reprogramming, and epithelial-mesenchymal transition (EMT). BCSCs harness autophagy to maintain stemness properties, evade immune surveillance, and resist therapeutic interventions. Conversely, excessive, or dysregulated autophagy may lead to BCSC differentiation or cell death, offering a potential avenue for therapeutic exploration. The molecular mechanisms that regulate autophagy in BCSCs including the mammalian target of rapamycin (mTOR), AMPK, and Beclin-1 signaling pathways may be potential targets for pharmacological intervention in breast cancer. This review provides a comprehensive overview of the relationship between autophagy and BCSCs, highlighting recent advancements in our understanding of their interplay. We also discuss the current state of autophagy-targeting agents and their preclinical and clinical development in BCSCs.

Keywords:  Autophagy; Breast Cancer; Breast Cancer stem cells; Metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1080/27694127.2024.2358648